The present invention is directed to the provision of compounds having potent anti-proliferative and anti-oxidant activity. The invention is further directed to compositions containing the compounds of the present invention for use in pharmaceutical applications. The present invention is also directed to various methods of using the compounds and compositions of the present invention in pharmaceutical applications including: 1) the treatment of inflammatory disorders including ocular inflammation associated with ophthalmic disease and ophthalmic surgery; 2) the prevention of corneal haze following ocular surgery; 3) tissue preservation including cornea preservation during transplantation procedures; and 4) as an adjunct to heart disease therapy. These compounds may find special utility in ocular indication such cataract formation following ocular surgery including secondary cataract following IOL implantation, cataract formation associated with chronic uveitis, reduction in the rate of regression of correction following laser surgery to correct vision defects, regrowth of pterygium following removal, arresting the rate of neovascularization caused by conditions such as diabetic retinopathy, or the wet form of macular degeneration. Systemic application of this compound might reduce the formation and rate of progression of atherosclerotic lesion or other vascular inflammatory pathologies.
Inflammation from cellular stress can cause excessive tissue damage. Numerous biochemical pathways are known to lead to inflammation. In general, the cyclooxygenase system produces prostaglandins, while the lipoxygenase system produces leukotrienes, "HETES" and "HPETEs". Such agents have been associated with inflammation. See generally, Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 600-617, Pergman Press, NY (1990). Therapies designed to inhibit the production of these types of agents are therefore of great interest.
Non-steroidal anti-inflammatory agents ("NSAIA") have been used for the treatment of inflammatory disorders. The following references may be referred to for further background concerning this use of NSAIAs:
Ophthalmoscope, volume 8, page 257 (1910);
Nature, volume 231, page 232 (1971);
FASEB Journal volume 1, page 89 (1987); and
Inflammation and Mechanisms and Actions of Traditional Drugs, Vol. I
Anti-inflammatory and Anti-rheumatic drugs. Boca Raton, FL, CRC Press, (1985).
However, there are some problems associated with NSAIA treatment including delivery to the appropriate site of action and side effects (Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 638-669, Pergman Press, NY (1990)).
Free radical molecules also play a major role in inflammation. These unstable chemical moieties lead to the oxidation of tissue resulting in damage. Such oxidative stress and damage has been described in Biochemical Pharmacology, 32(14), 2283-2286 (1983) and Free Radicals in Biology and Medicine, 4, 225-261 (1988). Agents that act as anti-oxidants can protect against oxidative damage. Such protection has been the subject of numerous scientific publications, including the following:
Archives of Pharmacology, volume 325, pages 129-146 (1992);
Journal of Photochemistry and Photobiology, volume 8, pages 211-224 (1991);
Free Radicals in Biology and Medicine, volume 11, pages 215-232 (1991); and
European Journal of Pharmacology, volume 210, pages 85-90 (1992).
The combination of anti-oxidant activity with other pharmacologically significant activities in a single molecule is discussed in JP 010484 A2 and EP 387771 A2; and compounds with cyclooxygenase/5-Lipoxygenase and anti-oxidant activity are discussed in Drug Research, 39(II) Number 10, pages 1242-1250 (1989). However, these references do not disclose the compounds of the present invention.
Ocular inflammation is a condition which generally affects the patient with scratchiness, itchiness and/or red eye. Ocular inflammation can be initiated by various insults. For example, ocular inflammation can result from allergic response to various allergens, trauma to the eye, dry eye and surgical complications. Various anti-inflammatory therapies are currently in use for the treatment of ocular inflammation including the topical administration of diclofenac.
Ocular surgery can result in various post-surgical complications to the eye. Such complications generally include: 1) loss of vascular blood barrier frinction; 2) tissue edema including conjunctiva swelling, conjuctiva conjestion and comneal haze; 3) cataract formation; and 4) loss of membrane integrity including decrease in docosahexanenoic acid levels in membrane phospholipids.
As stated above, vitrectomy surgery can induce a variety of post-surgical complications. Many of these complications are further potentiated in diabetic patients who are at risk for many ocular pathologies. Posterior segment surgery due to the severity of the surgical procedure can cause extensive tissue damage at both the acute and chronic phases of the recovery process. The acute phase of the postsurgical period is characterized by both ocular neovascularization and tissue edema. This is caused by breakdown of the blood aqueous and blood retinal barrier functions resulting in sustained vascular permeability following the surgical trauma. The presence of elevated inflammatory and serum factors induce cell proliferation during the normal wound healing process. Slitlamp clinical examinations at 24 hours have indicated extensive anterior chamber flare and cell influx, conjunctiva congestion and swelling (with discharge), iritis, and corneal haze. See for example, Kreiger, A. E., Wound Complications In Pars Plana Vitrectomy, Retina, volume 13, No. 4, pages 335-344 (1993); Cherfan, G. M., et al., Nuclear Sclerotic Cataract After Vitrectomy for Idiopathic Epiretinal Membranes Causing Macular Pucker, American Journal Of Ophthalmology, volume 111, pages 434-438 (1991); Thompson, J. T., et al., Progression of Nuclear Sclerosis and Long-term Visual Results of Virectomy With Transforming Growth Factor Beta-2 for Macular Holes, American Journal Of Ophthalmology, volume 119, pages 48-54 (1995) and Dobbs, R. E., et al., Evaluation Of Lens Changes In Idiopathic Epiretinal Membrane, volume 5, Nos. 1 & 2, pages 143-148 (1988).
The chronic phase of the postsurgical period is characterized by more severe complications that can necessitate additional surgery. These include an incidence of recurrent retinal detachment, epiretinal proliferation, neovascular glaucoma, corneal problems, vitreous hemorrhage, rate of cystoid macular edema, and occurrence of cataract formation within six months of surgery.
The frequency of these complications can be lessened by facilitating the recovery of vascular leakage and limiting the duration of the cellular proliferative response by introduction of therapeutic compounds into the irrigating solution during the time of surgery.
Organ or tissue tranplantation requires the preservation of the tissue from the time of excission from the donor to the time of transplantation into the recipient. During this time the tissue can become inflammed and even die. Methods of preserving the tissue have included the use of various temperature conditions, the use of chondroitin sulfate and the use of anti-inflammatory agents (Lindstrom, R. L., et al., Corneal Preservation at 4.degree. C. with Chondroitin Sulfate-Containing Medium, The Cornea: Transactions of the World Congress on the Cornea III, edited by H. Dwight Cavanagh, Raven Press, Ltd., New York, Chapter 14, pages 81-89 (1988); and Guo, A., et al., Effects of anti-inflammatory and immunosuppressive drugs on the heterolamellar corneal transplantation in rabbits, Current Eve Research, volumne 9, No. 8, pages 749-757 (1990)).
Oxidation of various biomolecules in the vasculature has been implicated in numerous cardiovascular pathologies including atherosclerosis, thrombosis, myocardial infarction and congestive heart failure. In particular, several reports demonstrate a correlation between the oxidation of low-density lipoproteins (LDL) and the progression of atherosclerotic lesions (New England Journal of Medicine, volume 328(20), pages 1444-1449 (1993)). These oxidized LDLs have been furher characterized in several pathological events including: 1) chemotaxis, which draws monocytes to the afflicted tissue; 2) differentiation of mdnocytes into macrophages; 3) uptake of LDL by macrophages to form foam cells; 4) proliferation of smooth muscle cells; 5) development of atherosclerotic lesions; and 6) cytotoxic effects on endothelial cells as well as increases in arterial vasoconstriction (JAMA, volume 264(3), pages 3047-3052 (1990)).
The use of antioxidants to ameliorate coronary heart disease has been explored. Epidemiological studies have correlated the dietary intake of Vitamin E with reduced risk to coronary heart disease (New England Journal of Medicine, volume 328(20), pages 1444-1449 (1993); and New England Journal of Medicine, volume 328(20), pages 1450-156 (1993)). .beta.-carotene, a naturally occuring anti-oxidant, has been pursued in the clinic for cardiovascular disease indications (Scrip No., 1574:31 (1990)). Additionally, research has shown that treatment of hypercholesterolemic animals with antioxidant drugs, including the phenolic antioxidant compound, probucol, has reduced the development of atherosclerosis (Proceedings of the National Academy of Science, U.S.A., volume 84, pages 7725-7729 (1989)).
Oxygen radicals have also been implicated in the pathogenesis of a number of other inflammatory conditions. Such conditions have included stroke, rheumatoid arthritis, retinopathy and endotoxic liver injury. It is believed that anti-oxidants would be useful in treating such conditions (Methods in Enzymology, volume 186, pages 1-85 (1990)).
Anti-inflammatory therapy has been suggested as an adjuvant to the treatment of various cardiovascular indications. These agents assist in preventing thrombotic and atherosclerotic occlusions and restenosis of the vasculature by inhibiting platelet and leukocyte aggregation.
As such, aspirin has been prescribed broadly, for anti-inflammatory and analgetic indications, as well as for patients with unstable angina. Ibuprofen and naproxen have been prescribed for treatment of rheumatoid arthritis and moderate pain. However, there are some problems associated with NSAIA treatment including delivery to the appropriate site of action and side effects (Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 638-669, Pergman Press, NY (1990)).
The present invention is directed to the provision of new compounds that have potent anti-inflammatory, anti-proliferative and anti-oxidant activity in a single molecule. The use of a single chemical entity with these potent activities provides increased protection relative to the use of a compound with singular activity. The use of a single agent having both activities over a combination of two or three different agents provides uniform delivery of an active molecule, thereby simplifying issues of drug metabolism, toxicity and delivery.